Safety and hemostatic efficacy of fibrin pad in partial nephrectomy: results of an open-label phase I and a randomized, standard-of-care-controlled phase I/II study

Abstract

Background: Bleeding severity, anatomic location, tissue characteristics, and visibility are common challenges encountered while managing intraoperative bleeding, and conventional hemostatic measures (suture, ligature, and cautery) may sometimes be ineffective or impractical. While topical absorbable hemostats (TAH) are useful hemostatic adjuvants, each TAH has associated disadvantages.

Methods: We evaluated the safety and hemostatic efficacy of a new advanced biologic combination product-fibrin pad-to potentially address some gaps associated with TAHs. Fibrin pad was assessed as adjunctive hemostat in open partial nephrectomy in single-center, open-label, Phase I study (N = 10), and as primary hemostat in multicenter, single-blind, randomized, standard-of-care (SOC)-controlled Phase I/II study (N = 7) in Israel. It was used to control mild-to-moderate bleeding in Phase I and also spurting arterial bleeding in Phase I/II study. Phase I study assessed safety and Phase I/II study, proportion of successes at 10 min following randomization, analyzed by Fisher exact tests at 5% significance level.

Results: Phase I (N = 10): All patients completed the study. Hemostasis was achieved within 3-4 min (average = 3.1 min) of a single application in all patients. Fibrin pad was found to be safe for human use, with no product-related adverse events reported. Phase I/II (N = 7): Hemostatic success at 10 min (primary endpoint) was achieved in 3/4 patients treated with fibrin pad versus 0/3 patients treated with SOC. No clinically significant change in laboratory or coagulation parameters was recorded, except a case of post-procedural hemorrhage with fibrin pad, which was considered serious and related to the fibrin pad treatment, and required re-operation. Although Data Safety Monitoring Board authorized trial continuation, the sponsor decided against proceeding toward an indication for primary treatment of severe arterial hemorrhage as a replacement for sutures. The study was suspended after 7/30 planned subjects were enrolled.

Conclusions: The first-in-man trial of fibrin pad demonstrated its safety and efficacy as an adjunctive hemostatic technique for mild-to-moderate bleeding in partial nephrectomy. The study also suggested that the product should not replace sutures or meticulous surgical techniques for the treatment of severe arterial hemorrhage.

Trial registration: Phase I/II trial, NCT00598130.

Figures

Figure 1

Scanning electron micrograph (SEM) image of fibrin pad. A) Top-view of fibrin pad, B) Cross section of bioactive matrix with human fibrinogen and human thrombin powders retained by polyglactin 910 fibers, and C) Image of the product application site during porcine partial nephrectomy.

Figure 2

Time-table for assessment of hemostasis. Time points were recorded from start of kidney resection to the observation period for both the studies. Time to hemostasis (TTH) and total time for hemostasis (TTTH) were calculated from these time points. *If complete hemostasis was not achieved at 3 min, up to 2 additional applications were permitted within the 10-min evaluation period, starting immediately after the 1st application, with the total fibrin pad used not exceeding a 10 x 10 cm2 unit. If hemostasis was not achieved during the 10-min evaluation period with 3 applications of fibrin pad, the patient was recorded as treatment failure and further hemostatic measures based on physician preference were employed.

Figure 3

Patient disposition of Phase I (Panel A) and Phase II (Panel B) studies.

Figure 4

Changes in hemoglobin and hematocrit levels from baseline to 12 h post-surgery in the Phase I open-label study. There was a mean drop of 0.86 g/dL in the hemoglobin level and 2.3% in the hematocrit level over this period.